Understanding the Risk

April 9, 2025 by Clare Whitewoods

The costs of not thinking ahead during early-stage development

This is the first in a three-part series based on our whitepaper, Set Your Cell and Gene Therapy Program Up for Success from Day One

The complexity and innovative nature of cell and gene therapies (CGT) means they are often discovered and initially developed in academic laboratories, translational institutes, or small biotech startups. These entities typically excel in scientific innovation but can lack experience in later stage development and commercialization.

Despite this, decisions made during early-phase discovery and development have important effects when it comes to the success of scaling to clinical and commercial stages. What is the magnitude of the risk of not thinking ahead, and what are some of the sources of this risk?

In our whitepaper, Set Your Cell and Gene Therapy Program Up for Success from Day One, we discuss the potential pitfalls and their associated costs, and how you can avoid them. This is the first of three blog posts providing an overview of what’s included in that whitepaper.

The impact of research reproducibility

Decisions on material selection, methods, and processes made during preclinical stages can significantly impact the reproducibility of early work. Not only does this pose a challenge to the progress of preclinical research, but it often leads to increased project timelines and costs, hindering program success in later phases.

One study estimated that over 50% of preclinical research can’t be replicated, resulting in approximately $28 billion annually wasted in the US alone, with the primary causes of low reproducibility linked to biological reagents and reference materials (36.1%), study design (27.6%), data analysis and reporting (25.5%), and laboratory protocols (10.8%).

Changes in processes and materials during development

Discovering that a material or process is unsuitable as a program progresses, for instance due to inability to meet cGMP quality standards and challenges with process scalability, can lead to major disruptions. These can include the addition of comparability studies and may result in a need to transfer to a new manufacturing partner, which is particularly challenging during Phase III clinical trials and regulatory submission.

A 2022 study of 90 CGTs that entered Phase III trials showed that 43% of CGTs experienced a disruption. Disruption increased as development progressed:

• 12% of CGTs that entered phase III were disrupted
• 47% of CGTs that completed phase III were disrupted
• 50% of those filed for FDA approval faced disruptions

Notably, Chemistry, Manufacturing, and Controls (CMC) issues were the main cause of disruptions during the regulatory review, accounting for 60% of disruptions at this stage. Two-thirds of all disruptions resulted in a delay of at least one year, adding significantly to development costs and delaying the commercial product launch.

Since changes in materials can lead to delays and disruptions, and even clinical holds, selecting the right reagents early in CGT development is crucial to avoid these issues later in the process. Not all reagents can be easily transitioned to clinical use due to intellectual property (IP) constraints or availability in the appropriate cGMP quality. By choosing fit-for-purpose reagents from the start, developers can mitigate these risks. Additionally, using standardized off-the-shelf (OTS) catalog products that are readily available in clinical-grade formulations ensures smoother scalability and regulatory compliance.

A history of program failure

Poor reproducibility in preclinical work and disruptions in clinical studies elevate the risk of program failure. Promising early-stage therapies may fail in large-scale clinical trials due to the inability to replicate results or issues with scaling up. Small details like incorrect potency assay procedures or small intricacies with ingredients can lead to failures with scaling up after successful Phase I and II readouts. Additionally, in a competitive funding environment, demonstrating scientific viability and scalability capabilities is crucial for securing investment.

Recent clinical trial failures highlight the risks associated with advancing to later stages. For example, Pfizer’s gene therapy for Duchenne muscular dystrophy failed to achieve its primary endpoint in a Phase III CIFFREO trial. Similarly, in 2021, Biogen’s two high-profile gene therapies for rare eye diseases failed in late-stage clinical trials, resulting in $542 million in impairment charges. In 2023, Takeda discontinued its AAV gene therapy programs, underscoring the high risk associated with gene therapy R&D and the fact that many current AAV programs may not reach late-stage trials.

The complexity of CGTs means that development will likely always be challenging. However, there are ways to minimize these risks, and thinking ahead from the very start of a program is an important start. In our next post, we’ll take a closer look at the potential pitfalls in the development process and how to work through them.

Learn more about setting your program up for success. Download our whitepaper today

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